2. Academic Validation
  3. Silencing of activating transcription factor 3 alleviates oxidative stress and inflammation and improves cognitive dysfunction in vascular dementia rats by repressing ferroptosis

Silencing of activating transcription factor 3 alleviates oxidative stress and inflammation and improves cognitive dysfunction in vascular dementia rats by repressing ferroptosis

  • Int Immunopharmacol. 2025 Jun 17:158:114730. doi: 10.1016/j.intimp.2025.114730.
Weina Gao 1,  Zuoxiao Li 2,  Caidi Yang 3,  Yan Lin 3,  Lijuan Wang 4
Affiliations

Affiliations

  • 1 Critical Care Medicine, 363 Hospital, 108 Daosangshu Street, Wuhou District, Chengdu City, Sichuan Province 610041, China.
  • 2 Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
  • 3 Department of Neurology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
  • 4 Department of Neurology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. Electronic address: Wangljuann@163.com.
PMID: 40347885 DOI: 10.1016/j.intimp.2025.114730
Abstract

Objective: Vascular dementia (VaD) is an acquired cognitive dysfunction syndrome. The aim of this study is to explore whether activating transcription factor 3 (ATF3) regulates Ferroptosis through the Nrf2 pathway, thereby affecting cognitive impairment in VaD rats.

Methods: The rats rendered with VaD through bilateral common carotid artery occlusion modeling were injected with siR ATF3 lentivirus. Rat cognitive/learning functions and motor disorder were evaluated by Morris water maze and open field tests, and pathological changes in the rat hippocampus were tested by H&E staining. Levels of neurotransmitters [acetylcholine (ACH)/dopamine (DA)] and ATF3 in the hippocampus were assessed by ELISA/RT-qPCR/Western blot. Iron content, SOD/GSH-Px activities, MDA/ROS levels, ferroptosis-related molecules, and inflammatory proteins in rat hippocampus tissues were also detected. H19-7 cells were induced by a ferroptosis-specific inhibitor (ferrostatin-1), treated with hypoxia, and manipulated with sh-ATF3. Based on ATF3 silencing, H19-7 cells were treated with the Nrf2 pathway inhibitor for in-depth mechanism validation.

Results: ATF3 was found to be highly expressed in VaD rat hippocampus, while its silencing improved cognitive dysfunction and resulted in repressed Ferroptosis in the hippocampus, reduced iron content and COX2, and upregulated SLC7A11/GPX4, thus alleviating inflammatory reaction and oxidative stress in VaD rat hippocampus. Moreover, ATF3 knockdown suppressed Ferroptosis in H19-7 cells, activated the Nrf2 pathway, and promoted Nrf2 nuclear translocation. However, Nrf2 pathway inactivation was unveiled to counteract the anti-ferroptosis effect of ATF3 silencing on hypoxia-stimulated H19-7 cells.

Conclusion: ATF3 knockdown alleviated oxidative stress and inflammatory reaction in VaD rat hippocampus by suppressing Ferroptosis, thus improving cognitive dysfunction.

Keywords

Activating transcription factor 3; Cognitive dysfunction; Ferroptosis; H19–7 cells; Hippocampus; Inflammatory reaction; Nrf2 pathway; Oxidative stress; Vascular dementia.

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